The study aimed to design, synthesize and evaluate various brominated derivatives of 7-hydroxy coumarin as a new scaffold against Alzheimer’s disease by in vivo and in vitro models. A group of three novel pyrazoles endowed with brominated 7-hydroxy 4-methyl coumarin derivatives were designed. Among the designed compounds, a single entity (D1) was selected based on the docking score, which could be considered mainly for the treatment of Alzheimer’s disease. Three novel pyrazoles endowed with brominated 7-hydroxy 4-methyl coumarin derivatives were designed and docking studies of these compounds were carried out using Argus lab4.0.1 version. According to the docking score, a single entity of compound (D1) was selected for further study. The structure of the compound (D1) was explored by spectral analysis. The anti-Alzheimer’s activity was evaluated by in vivo and in vitro methods. All results were compared statistically by one-way ANOVA using GraphPad Prism. Molecular docking studies revealed that the compound D1 was able to bind simultaneously to the amino acid and in the active sites of the acetylcholine esterase enzyme. In acetylcholine esterase inhibition assay, the compound shows a significant increase in acetylcholine esterase level. The MAO inhibitory activities were in the nanomole range (human MAO-A IC50 = 3.9, human MAO-B IC 50 = 4.4). DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assay showed that the compound shows a promising antioxidant property. In the evaluation of learning and memory of compound D1 using elevated plus maze, the compound D1-pretreated group showed a significant increase in memory and learning when compared with donepezil. Among the designed series of pyrazole endowed with brominated 7-hydroxyl 4-methyl coumarin derivatives, compound D1 showed good antioxidant property and acetylcholine esterase and MAO inhibitory activity; based on this property, the synthesized compound D1 can be considered a new scaffold on Alzheimer’s disease.

中文翻译：

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具有溴化 4-甲基 7-羟基香豆素的取代吡唑作为抗阿尔茨海默病新支架的设计、合成和生物学评价

该研究旨在通过体内和体外模型设计、合成和评估 7-羟基香豆素的各种溴化衍生物作为抗阿尔茨海默病的新支架。设计了一组具有溴化 7-羟基 4-甲基香豆素衍生物的三种新型吡唑。在设计的化合物中，根据对接评分选择了单一实体（D1），可以考虑主要用于治疗阿尔茨海默病。设计了三种具有溴化7-羟基4-甲基香豆素衍生物的新型吡唑，并使用Argus lab4.0.1版本对这些化合物进行对接研究。根据对接分数，选择单一实体化合物（D1）进行进一步研究。通过光谱分析探索化合物(D1)的结构。通过体内和体外方法评估抗阿尔茨海默病的活性。使用 GraphPad Prism 通过单向方差分析对所有结果进行统计比较。分子对接研究表明，化合物 D1 能够同时结合氨基酸和乙酰胆碱酯酶的活性位点。在乙酰胆碱酯酶抑制试验中，该化合物显示乙酰胆碱酯酶水平显着增加。MAO 抑制活性在纳摩尔范围内（人 MAO-A IC50 = 3.9，人 MAO-B IC 50 = 4.4）。DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) 测定表明该化合物具有良好的抗氧化性能。在使用高架十字迷宫评估化合物 D1 的学习和记忆中，与多奈哌齐相比，化合物 D1 预处理组的记忆和学习能力显着提高。在设计的具有溴化7-羟基4-甲基香豆素衍生物的吡唑系列中，化合物D1表现出良好的抗氧化性和乙酰胆碱酯酶和MAO抑制活性；基于这一特性，合成的化合物D1可以被认为是阿尔茨海默病的新支架。